Abstract
The TCIRG1 gene encodes the a3 isoform of vacuolar H+-ATPase (V-ATPase), which forms a proton transport channel in osteoclasts. Defects in this gene lead to functional impairment of osteoclasts and increased bone mass; however, the molecular mechanisms of TCIRG1 loss have not been fully elucidated. In the current study, we transfected mouse bone marrow-derived monocytes with control or Tcirg1-knockdown lentiviruses to further investigate the mechanisms of TCIRG1. Our results demonstrate that knockdown of Tcirg1 inhibits large-osteoclast (>100 μm) generation by decreasing the expression of nuclear factor of activated T-cells 1 (NFATc1) and inositol-1,4,5-trisphosphate receptor 2 (IP3R2). The decreased IP3R2 reduces intracellular calcium levels, which limits the nuclear translocation of NFATc1 in RANKL-induced mouse bone marrow-derived monocytes. These findings provide a mechanism to explain the effects of TCIRG1 impairment, with potential implications for the development of therapies for osteopetrosis.
Highlights
Osteoclasts are derived from mononuclear progenitors of pluripotent hematopoietic stem cells
These results suggest that Tcirg1 knockdown decreases Lamp2 and V-ATPase expression, leading to smaller osteoclasts
We found that the expression of IP3R2 was decreased in Tcirg1-knockdown osteoclasts and that the level of intracellular Ca2+ oscillation was decreased, suggesting that the reduced nuclear factor of activated T-cells 1 (NFATc1) nuclear translocation levels may be explained by reduced intracellular Ca2+
Summary
Osteoclasts are derived from mononuclear progenitors of pluripotent hematopoietic stem cells. Their main function relates to the resorption of mineralized tissues, such as bone. Osteoclasts are critical for the maintenance, repair and remodeling of bones, and any defect in osteoclasts would lead to an increase in bone mass [1]. V-ATPase is a highly conserved enzyme complex that is important for osteoclast function [3]. It is comprised of the proton translocation domain V0, which contains a, c, c’, d and e subunits, as well as the ATP hydrolysis domain V1, which contains A-H subunits.
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